Specific Interaction with Cardiolipin Triggers Functional Activation of Dynamin-Related Protein 1

Dynamin-Related Protein 1 (Drp1), a large GTPase of the dynamin superfamily, is required for mitochondrial fission in healthy and apoptotic cells. Drp1 activation is a complex process that involves translocation from the cytosol to the mitochondrial outer membrane (MOM) and assembly into rings/spirals at the MOM, leading to membrane constriction/division. Similar to dynamins, Drp1 contains GTPase (G), bundle signaling element (BSE) and stalk domains. However, instead of the lipid-interacting Pleckstrin Homology (PH) domain present in the dynamins, Drp1 contains the so-called B insert or variable domain that has been suggested to play an important role in Drp1 regulation. Different proteins have been implicated in Drp1 recruitment to the MOM, although how MOM-localized Drp1 acquires its fully functional status remains poorly understood. We found that Drp1 can interact with pure lipid bilayers enriched in the mitochondrion-specific phospholipid cardiolipin (CL). Building on our previous study, we now explore the specificity and functional consequences of this interaction. We show that a four lysine module located within the B insert of Drp1 interacts preferentially with CL over other anionic lipids. This interaction dramatically enhances Drp1 oligomerization and assembly-stimulated GTP hydrolysis. Our results add significantly to a growing body of evidence indicating that CL is an important regulator of many essential mitochondrial functions.

Activation of violaxanthin cycle in darkness is a common response to different abiotic stresses : a case study in Pelvetia canaliculata

Background: In the violaxanthin (V) cycle, V is de-epoxidized to zeaxanthin (Z) when strong light or light combined with other stressors lead to an overexcitation of photosystems. However, plants can also suffer stress in darkness and recent reports have shown that dehydration triggers V-de-epoxidation in the absence of light. In this study, we used the highly stress-tolerant brown alga Pelvetia canaliculata as a model organism, due to its lack of lutein and its non-photochemical quenching independent of the transthylakoidal-ΔpH, to study the triggering of the V-cycle in darkness induced by abiotic stressors. Results: We have shown that besides desiccation, other factors such as immersion, anoxia and high temperature also induced V-de-epoxidation in darkness. This process was reversible once the treatments had ceased (with the exception of heat, which caused lethal damage). Irrespective of the stressor applied, the resulting de-epoxidised xanthophylls correlated with a decrease in Fv/Fm, suggesting a common function in the down-regulation of photosynthetical efficiency. The implication of the redox-state of the plastoquinone-pool and of the differential activity of V-cycle enzymes on V-de-epoxidation in darkness was also examined. Current results suggest that both violaxanthin de-epoxidase (VDE) and zeaxanthin-epoxidase (ZE) have a basal constitutive activity even in darkness, being ZE inhibited under stress. This inhibition leads to Z accumulation. Conclusion: This study demonstrates that V-cycle activity is triggered by several abiotic stressors even when they occur in an absolute absence of light, leading to a decrease in Fv/Fm. This finding provides new insights into an understanding of the regulation mechanism of the V-cycle and of its ecophysiological roles.

The Oxidative State of Chylomicron Remnants Influences Their Modulation of Human Monocyte Activation

8 p.

A Model of Ischemia-Induced Neuroblast Activation in the Adult Subventricular Zone

12 p.

USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

12 p.

GABAergic and Cortical and Subcortical Glutamatergic Axon Terminals Contain CB1 Cannabinoid Receptors in the Ventromedial Nucleus of the Hypothalamus

Background: Type-1 cannabinoid receptors (CB1R) are enriched in the hypothalamus, particularly in the ventromedial hypothalamic nucleus (VMH) that participates in homeostatic and behavioral functions including food intake. Although CB1R activation modulates excitatory and inhibitory synaptic transmission in the brain, CB1R contribution to the molecular architecture of the excitatory and inhibitory synaptic terminals in the VMH is not known. Therefore, the aim of this study was to investigate the precise subcellular distribution of CB1R in the VMH to better understand the modulation exerted by the endocannabinoid system on the complex brain circuitries converging into this nucleus. Methodology/Principal Findings: Light and electron microscopy techniques were used to analyze CB1R distribution in the VMH of CB1R-WT, CB1R-KO and conditional mutant mice bearing a selective deletion of CB1R in cortical glutamatergic (Glu-CB1R-KO) or GABAergic neurons (GABA-CB1R-KO). At light microscopy, CB1R immunolabeling was observed in the VMH of CB1R-WT and Glu-CB1R-KO animals, being remarkably reduced in GABA-CB1R-KO mice. In the electron microscope, CB1R appeared in membranes of both glutamatergic and GABAergic terminals/preterminals. There was no significant difference in the percentage of CB1R immunopositive profiles and CB1R density in terminals making asymmetric or symmetric synapses in CB1R-WT mice. Furthermore, the proportion of CB1R immunopositive terminals/preterminals in CB1R-WT and Glu-CB1R-KO mice was reduced in GABA-CB1R-KO mutants. CB1R density was similar in all animal conditions. Finally, the percentage of CB1R labeled boutons making asymmetric synapses slightly decreased in Glu-CB1R-KO mutants relative to CB1R-WT mice, indicating that CB1R was distributed in cortical and subcortical excitatory synaptic terminals. Conclusions/Significance: Our anatomical results support the idea that the VMH is a relevant hub candidate in the endocannabinoid-mediated modulation of the excitatory and inhibitory neurotransmission of cortical and subcortical pathways regulating essential hypothalamic functions for the individual's survival such as the feeding behavior.

Neurotransmitter signaling in the pathophysiology of microglia

Erratun publicado en Frontiers in Cellular Neuroscience 7 : (2013) // Article ID 107

Daily scale wintertime sea surface temperature and IPC-Navidad variability in the southern Bay of Biscay from 1981 to 2010

The combination of remotely sensed gappy Sea surface temperature (SST) images with the missing data filling DINEOF (data interpolating empirical orthogonal functions) technique, followed by a principal component analysis of the reconstructed data, has been used to identify the time evolution and the daily scale variability of the wintertime surface signal of the Iberian Poleward Current (IPC), or Navidad, during the 1981-2010 period. An exhaustive comparison with the existing bibliography, and the vertical temperature and salinity profiles related to its extremes over the Bay of Biscay area, show that the obtained time series accurately reflect the IPC-Navidad variability. Once a time series for the evolution of the SST signal of the current over the last decades is well established, this time series is used to propose a physical mechanism in relation to the variability of the IPC-Navidad, involving both atmospheric and oceanic variables. According to the proposed mechanism, an atmospheric circulation anomaly observed in both the 500 hPa and the surface levels generates atmospheric surface level pressure, wind-stress and heat-flux anomalies. In turn, those surface level atmospheric anomalies induce mutually coherent SST and sea level anomalies over the North Atlantic area, and locally, in the Bay of Biscay area. These anomalies, both locally over the Bay of Biscay area and over the North Atlantic, are in agreement with several mechanisms that have separately been related to the variability of the IPC-Navidad, i.e. the south-westerly winds, the joint effect of baroclinicity and relief (JEBAR) effect, the topographic beta effect and a weakened North Atlantic gyre.

Ca2+ Influx and Tyrosine Kinases Trigger Bordetella Adenylate Cyclase Toxin (ACT) Endocytosis. Cell Physiology and Expression of the CD11b/CD18 Integrin Major Determinants of the Entry Route

Humans infected with Bordetella pertussis, the whooping cough bacterium, show evidences of impaired host defenses. This pathogenic bacterium produces a unique adenylate cyclase toxin (ACT) which enters human phagocytes and catalyzes the unregulated formation of cAMP, hampering important bactericidal functions of these immune cells that eventually cause cell death by apoptosis and/or necrosis. Additionally, ACT permeabilizes cells through pore formation in the target cell membrane. Recently, we demonstrated that ACT is internalised into macrophages together with other membrane components, such as the integrin CD11b/CD18 (CR3), its receptor in these immune cells, and GM1. The goal of this study was to determine whether ACT uptake is restricted to receptor-bearing macrophages or on the contrary may also take place into cells devoid of receptor and gain more insights on the signalling involved. Here, we show that ACT is rapidly eliminated from the cell membrane of either CR3-positive as negative cells, though through different entry routes, which depends in part, on the target cell physiology and characteristics. ACT-induced Ca2+ influx and activation of non-receptor Tyr kinases into the target cell appear to be common master denominators in the different endocytic strategies activated by this toxin. Very importantly, we show that, upon incubation with ACT, target cells are capable of repairing the cell membrane, which suggests the mounting of an anti-toxin cell repair-response, very likely involving the toxin elimination from the cell surface.

Novel mechanisms for regulation of cell survival and migration by ceramide 1-phosphate

201 p. : gráf.

NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation

7 p.

Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields, surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built: (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (19972001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributed to the analogues-calculation stage.

Magnetization reversal and exchange bias effects in hard/soft ferromagnetic bilayers with orthogonal anisotropies

21 p.

Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease

The formation of cerebral senile plaques composed of amyloid beta peptide (A beta) is a fundamental feature of Alzheimer's disease (AD). Glial cells and more specifically microglia become reactive in the presence of A beta. In a triple transgenic model of AD (3 x Tg-AD), we found a significant increase in activated microglia at 12 (by 111%) and 18 (by 88%) months of age when compared with non-transgenic (non-Tg) controls. This microglial activation correlated with A beta plaque formation, and the activation in microglia was closely associated with A beta plaques and smaller A beta deposits. We also found a significant increase in the area density of resting microglia in 3 x Tg-AD animals both at plaque-free stage (at 9 months by 105%) and after the development of A plaques (at 12 months by 54% and at 18 months by 131%). Our results show for the first time that the increase in the density of resting microglia precedes both plaque formation and activation of microglia by extracellular A beta accumulation. We suggest that AD pathology triggers a complex microglial reaction: at the initial stages of the disease the number of resting microglia increases, as if in preparation for the ensuing activation in an attempt to fight the extracellular A beta load that is characteristic of the terminal stages of the disease. Cell Death and Disease (2010) 1, e1; doi:10.1038/cddis.2009.2; published online 14 January 2010

Literature Review of Integrated Impact Assessment Models of Climate Change with Emphasis on Damage Functions

35 p.